Daunorubicin (also known as daunomycin), doxorubicin (also known as Adriamycin), Aclacinomycin A and other cationic anthracycline anti-neoplastic agents are currently of great clinical interest for the treatment of tumors, including most leukemias and solid tumors. Structurally, these compounds consist of a hydrophobic tetracycline ring system coupled to an amino sugar through a glycoside linkage. These anthracycline agents associate with phosphate containing materials, and exhibit a high affinity with, for example, cardiolipin. These compounds have been shown to exhibit marked activity against a wide variety of neoplasms. However, the clinical use of these drugs in humans has been limited by the chronic toxic effect of the drugs on heart tissue. Children for example, are highly susceptible to doxorubicin-induced congestive heart failure. Mosijezuk, et al., Cancer, 44, p. 1582-1587 (1979). Long-term administration of such drugs leads to an increased risk of cardiomyopathy. Lefrak et al., Cancer, 32, p. 302-314 (1973).
Phospholipid bilayer membrane particles in the form of unilamellar vesicles known as liposomes have received increasing attention as possible carriers for anthracycline drugs. Certain formulations have been shown to increase antitumor activity, alter in vivo tissue distribution and decreas toxicity.
Difficulties have been encountered in producing encapsulated anthracyclines. In part this has been due to the surfactant or detergent-like effect these compounds exert on the phospholipid vesicle bilayer, causing leakage and creating vesicle instability. Another problem has been the aggregation of such vesicles during storage. In addition, the efficiency of entrapment of previous formulations of encapsulated anthracyclines has been low, and has been reported to be between 5 and 65%. Forssen and Tokes, Cancer Res. 43, p. 546-550 (1983); and Gabizon et al., Cancer Res. 43, p. 4730-4735 (1983); and Gabizon et al., Br. J. Cancer 51, p. 681-689 (1985). Thus it has not been possible to achieve large scale production of stable, encapsulated anthracyclines for therapeutic purposes.
Accordingly, it is an object of the present invention to provide improved formulations for encapsulating anthracycline anti-neoplastic agents in phospholipid bilayer membrane particles.
Another object of this invention is to provide a method fo using improved formulations of encapsulated anti-neoplastic agents to provide decreased cardiotoxicity and increased antitumor efficacy in humans.
The manner in which these and other objects are realized by the present invention will be apparent from the summary and detailed description set forth below.